We have employed a fragment‐based screen against wild‐type (NL4‐3) HIV protease (PR) using the Active Sight fragment library and X‐ray crystallography. The experiments reveal two new binding sites for small molecules. PR was co‐crystallized with fragments, or crystals were soaked in fragment solutions, using five crystal forms, and 378 data sets were collected to 2.3–1.3 Å resolution. Fragment binding induces a distinct conformation and specific crystal form of TL‐3 inhibited PR during co‐crystallization. One fragment, 2‐methylcyclohexanol, binds in the ‘exo site’ adjacent to the Gly16
Gly17
Gln18
loop where the amide of Gly17
is a specific hydrogen bond donor, and hydrophobic contacts occur with the side chains of Lys14
and Leu63
. Another fragment, indole‐6‐carboxylic acid, binds on the ‘outside/top of the flap’ via hydrophobic contacts with Trp42
, Pro44
, Met46
, and Lys55
, a hydrogen bond with Val56
, and a salt‐bridge with Arg57
. 2‐acetyl‐benzothiophene also binds at this site. This study is the first fragment‐based crystallographic screen against HIV PR, and the first time that fragments were screened against an inhibitor‐bound drug target to search for compounds that both bind to novel sites and stabilize the inhibited conformation of the target.